Effect of a prolyl endopeptidase inhibitor, JTP-4819, on radial maze performance in hippocampal-lesioned rats.
The effect of a novel prolyl endopeptidase (PEP) inhibitor, (S)-2-2[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl) -1-pyrrolidinecarboxamide (JTP-4819), on spatial learning deficits in rats with dorsal hippocampal (DH) lesions was examined using an eight-arm radial maze. The correct performance remained at chance levels even after 18 acquisition trials in rats with DH lesions. JTP-4819 (3.0 mg/kg, p.o.) significantly ameliorated this learning impairment after 34-41 days of treatment. When DH lesions were created in rats after achievement of learning, postoperative performance deteriorated prominently, but gradually recovered with the repetition of trials. JTP-4819 (3.0 mg/kg, p.o.) significantly decreased the number of trials needed to reattain learning criterion. After the behavioral experiment, the choline acetyltransferase (ChAT) activity and [3H]-pirenzepine binding (Kd, Bmax) in the residual hippocampus and cerebral cortex were analyzed. Neither parameter was significantly affected by JTP-4819. In conclusion, JTP-4819 can improve both learning and relearning deficits of spatial memory in DH-lesioned rats, postulating that enhancement of neuropeptide activity via PEP inhibition may be involved in the mechanism of action of JTP-4819.
Miyazaki
A
A
Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka.
Toide
K
K
Sasaki
Y
Y
Ichitani
Y
Y
Iwasaki
T
T
D000818:Animals; D001479:Basal Ganglia / Q000502:physiology; D002540:Cerebral Cortex / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D006624:Hippocampus / Q000033:anatomy & histology / Q000201:enzymology / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D010890:Pirenzepine / Q000378:metabolism; D000085822:Prolyl Oligopeptidases; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
D011759:Pyrrolidines; D011976:Receptors, Muscarinic; D015842:Serine Proteinase Inhibitors; D010890:Pirenzepine; C094211:JTP 4819; D002795:Choline O-Acetyltransferase; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases